Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Journal article

J. Barc, R. Tadros, C. Glinge, David Y. Chiang, Mariam Jouni, F. Simonet, S. Jurgens, M. Baudic, Michele Nicastro, F. Potet, J. Offerhaus, R. Walsh, S. Choi, A. Verkerk, Y. Mizusawa, S. Anys, Damien Minois, M. Arnaud, J. Duchâteau, Y. Wijeyeratne, A. Muir, M. Papadakis, S. Castelletti, M. Torchio, Cristina Gil Ortuño, J. Lacunza, D. Giachino, N. Cerrato, Raphael P. Martins, Ó. Campuzano, S. Van Dooren, A. Thollet, F. Kyndt, A. Mazzanti, N. Clementy, A. Bisson, A. Corveleyn, B. Stallmeyer, S. Dittmann, J. Saenen, Antoine Noël, Shohreh Honarbakhsh, B. Rudic, H. Marzak, M. Rowe, C. Federspiel, S. Le Page, L. Placide, A. Milhem, H. Barajas-Martinez, B. Beckmann, I. Krapels, J. Steinfurt, B. Winkel, R. Jabbari, M. Shoemaker, B. Boukens, Doris Škorić-Milosavljević, H. Bikker, Federico Manevy, P. Lichtner, M. Ribasés, T. Meitinger, M. Müller-Nurasyid, Konstantin Annette Holger Lars Reiner Margit Strauch Peters Schulz Schwettmann Leidl Heier, K. Strauch, Annette Peters, H. Schulz, L. Schwettmann, R. Leidl, M. Heier, J. Veldink, L. H. van den Berg, P. van Damme, D. Cusi, C. Lanzani, S. Rigade, Eric Charpentier, E. Baron, S. Bonnaud, S. Lecointe, Audrey Donnart, H. Le Marec, S. Chatel, Matilde Karakachoff, S. Bézieau, B. London, J. Tfelt‐Hansen, D. Roden, K. Odening, M. Cerrone, L. Chinitz, P. Volders, Maarten P. van de Berg, G. Laurent, L. Faivre, C. Antzelevitch, S. Kääb, A. A. Arnaout, J. Dupuis, J. Pasquié, O. Billon, Jason D. Roberts, L. Jesel, M. Borggrefe, P. Lambiase, J. Mansourati, B. Loeys, A. Leenhardt, P. Guicheney, P. Maury, E. Schulze-Bahr, T. Robyns, J. Breckpot, D. Babuty, S. Priori, C. Napolitano, Pascal Frédéric Jean Philippe François Defaye Anselme Darmon Wiart, P. Defaye, F. Anselme, J. Darmon, F. Wiart, C. de Asmundis, P. Brugada, R. Brugada, E. Arbelo, J. Brugada, P. Mabo, N. Béhar, C. Giustetto, M. S. Molina, J. Gimeno, C. Hasdemir, P. Schwartz, L. Crotti, P. McKeown, Sanjay Sharma, E. Behr, M. Haissaguerre, F. Sacher, C. Rooryck, H. Tan, C. Remme, P. Postema, M. Delmar, P. Ellinor, S. Lubitz, J. Gourraud, M. Tanck, Alfred L. George, C. Macrae, P. Burridge, C. Dina, V. Probst, A. Wilde, J. Schott, R. Redon, C. Bezzina
Nature Genetics, 2022

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Barc, J., Tadros, R., Glinge, C., Chiang, D. Y., Jouni, M., Simonet, F., … Bezzina, C. (2022). Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. Nature Genetics.

Chicago/Turabian Click to copy
Barc, J., R. Tadros, C. Glinge, David Y. Chiang, Mariam Jouni, F. Simonet, S. Jurgens, et al. “Genome-Wide Association Analyses Identify Novel Brugada Syndrome Risk Loci and Highlight a New Mechanism of Sodium Channel Regulation in Disease Susceptibility.” Nature Genetics (2022).

MLA Click to copy
Barc, J., et al. “Genome-Wide Association Analyses Identify Novel Brugada Syndrome Risk Loci and Highlight a New Mechanism of Sodium Channel Regulation in Disease Susceptibility.” Nature Genetics, 2022.

BibTeX Click to copy

@article{j2022a,
  title = {Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility},
  year = {2022},
  journal = {Nature Genetics},
  author = {Barc, J. and Tadros, R. and Glinge, C. and Chiang, David Y. and Jouni, Mariam and Simonet, F. and Jurgens, S. and Baudic, M. and Nicastro, Michele and Potet, F. and Offerhaus, J. and Walsh, R. and Choi, S. and Verkerk, A. and Mizusawa, Y. and Anys, S. and Minois, Damien and Arnaud, M. and Duchâteau, J. and Wijeyeratne, Y. and Muir, A. and Papadakis, M. and Castelletti, S. and Torchio, M. and Ortuño, Cristina Gil and Lacunza, J. and Giachino, D. and Cerrato, N. and Martins, Raphael P. and Campuzano, Ó. and Dooren, S. Van and Thollet, A. and Kyndt, F. and Mazzanti, A. and Clementy, N. and Bisson, A. and Corveleyn, A. and Stallmeyer, B. and Dittmann, S. and Saenen, J. and Noël, Antoine and Honarbakhsh, Shohreh and Rudic, B. and Marzak, H. and Rowe, M. and Federspiel, C. and Page, S. Le and Placide, L. and Milhem, A. and Barajas-Martinez, H. and Beckmann, B. and Krapels, I. and Steinfurt, J. and Winkel, B. and Jabbari, R. and Shoemaker, M. and Boukens, B. and Škorić-Milosavljević, Doris and Bikker, H. and Manevy, Federico and Lichtner, P. and Ribasés, M. and Meitinger, T. and Müller-Nurasyid, M. and Heier, Konstantin Annette Holger Lars Reiner Margit Strauch Peters Schulz Schwettmann Leidl and Strauch, K. and Peters, Annette and Schulz, H. and Schwettmann, L. and Leidl, R. and Heier, M. and Veldink, J. and van den Berg, L. H. and van Damme, P. and Cusi, D. and Lanzani, C. and Rigade, S. and Charpentier, Eric and Baron, E. and Bonnaud, S. and Lecointe, S. and Donnart, Audrey and Marec, H. Le and Chatel, S. and Karakachoff, Matilde and Bézieau, S. and London, B. and Tfelt‐Hansen, J. and Roden, D. and Odening, K. and Cerrone, M. and Chinitz, L. and Volders, P. and van de Berg, Maarten P. and Laurent, G. and Faivre, L. and Antzelevitch, C. and Kääb, S. and Arnaout, A. A. and Dupuis, J. and Pasquié, J. and Billon, O. and Roberts, Jason D. and Jesel, L. and Borggrefe, M. and Lambiase, P. and Mansourati, J. and Loeys, B. and Leenhardt, A. and Guicheney, P. and Maury, P. and Schulze-Bahr, E. and Robyns, T. and Breckpot, J. and Babuty, D. and Priori, S. and Napolitano, C. and Wiart, Pascal Frédéric Jean Philippe François Defaye Anselme Darmon and Defaye, P. and Anselme, F. and Darmon, J. and Wiart, F. and de Asmundis, C. and Brugada, P. and Brugada, R. and Arbelo, E. and Brugada, J. and Mabo, P. and Béhar, N. and Giustetto, C. and Molina, M. S. and Gimeno, J. and Hasdemir, C. and Schwartz, P. and Crotti, L. and McKeown, P. and Sharma, Sanjay and Behr, E. and Haissaguerre, M. and Sacher, F. and Rooryck, C. and Tan, H. and Remme, C. and Postema, P. and Delmar, M. and Ellinor, P. and Lubitz, S. and Gourraud, J. and Tanck, M. and George, Alfred L. and Macrae, C. and Burridge, P. and Dina, C. and Probst, V. and Wilde, A. and Schott, J. and Redon, R. and Bezzina, C.}
}

Abstract

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism.